BCL11B targeting in tumor CD8+ T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity

Tumor-infiltrating CD8+ T cells often become terminally exhausted (Ttex), losing functionality and renewal capacity, while their precursors (Tpex) retain stemness and can generate effective effectors. The authors observed that melanoma patients responding better to checkpoint inhibitor therapy had lower BCL11B mRNA in their T cells. In mouse melanoma and ovarian cancer models, genetic ablation of Bcl11b in CD8+ T cells produced superior anti-tumor responses. Bcl11b knockout (KO) TILs remained in a stem-like state and failed to fully differentiate into Ttex cells. Mechanistically, BCL11B repressed transcription factors that control stemness while promoting exhaustion-associated transcription factors and inhibitory receptors via epigenetic regulation. BCL11B KO CD8+ T cells also showed increased antigen-specific cytolytic activity and elevated granzyme B and perforin protein levels, without corresponding increases in their mRNAs, but with higher expression of translation-related genes. In human TILs from a patient who responded poorly to adoptive cell therapy, CRISPR-Cas9 deletion of BCL11B enhanced cytolytic activity and increased expression of the stemness-associated transcription factor TCF1, suggesting that BCL11B targeting could improve T cell-based immunotherapies.